Acute promyelocytic leukemia (APL) (FAB M3) cases express the oncogenic product of the t(15; 17) chromosomal rearrangement, promyelocytic leukemia (PML)/retinoic acid receptor α (RAR α) (Nason-Burchenal, et al. (1996) In Molecular Biology of Cancer, ed. Bertino, Academic San Diego, 1st Ed., pp 1547-1560; Nason-Burchenal & Dmitrovsky (1999) In Retinoids: The Biochemical and Molecular Basis of Vitamin A and Retinoid Action, eds. Nau & Blaneer, Springer, Berlin, pp. 301-322). All-trans-retinoic acid (RA) treatment causes complete remissions in these APL cases through induction of leukemic cell differentiation (Nason-Burchenal et al. (1996) supra; Nason-Burchenal & Dmitrovsky (1999) supra). A hallmark of RA response in APL is PML/RARα degradation that reverses PML/RARα oncogenic effects (Kakizuka, et al. (1991) Cell 68:663-674; Yoshida, et al. (1996) Cancer Res. 56:2945-2948; Raelson, et al. (1996) Blood 88:2826-2832; Nervi, et al. (1998) Blood 92:2244-2251; Zhu, et al. (1999) Proc. Natl. Acad. Sci. USA 96:14807-14812). Proteasomal inhibitors prevent PML/RARα proteolysis, despite RA treatment, which is indicative of a proteasome-dependent pathway in this degradation (Yoshida, et al. (1996) supra; Raelson, et al. (1996) supra; Nervi et al. (1998) supra; Zhu, et al. (1999) supra). PML/RARα expression results in dominant-negative transcriptional repression (Kakizuka, et al. (1991) supra; de The, et al. (1991) Cell 68:675-684). This repression is antagonized by pharmacological RA dosages that overcome inhibitory effects on transcription of the N-Cor/SMRT corepressor complex that has histone deacetylase activity (Lin, et al. (1998) Nature (London) 391:811-814; Grignani, et al. (1998) Nature (London) 391:815-818). RA treatment recruits a coactivator complex that stimulates transcription, resulting in activation of target genes (Lin, et al. (1998) supra; Grignani, et al. (1998) supra).
To understand the molecular basis of RA response in APL, RA target gene identification has been sought. GOS2 has been suggested as a putative RA target gene as determined by microarray analysis of APL cells (Tamayo, et al. (1999) Proc. Natl. Acad. Sci. USA 96:2907-2912). The precise function of GOS2 is not yet known, but it was first identified as regulated during the cell cycle (Russell & Forsdyke (1991) DNA Cell Biol. 10:581-591), suggesting a role in cell cycle control.
Another candidate retinoid target gene is the CCAAT/enhancer binding protein epsilon (C/EBP epsilon) that contributes to retinoid transcriptional effects in APL (Park, et al. (1999) J. Clin. Invest. 103:1399-1408). However, this species has not been linked to the degradation of PML/RARα.
Recent microarray analysis of RA-treated NB4 APL cells reported the prominent induction of UBE1L (ubiquitin-activating enzyme E1-like) (Tamayo, et al. (1999) supra). The proteasome-dependent degradation of PML/RARα has also been proposed as a mechanism by which RA overcomes PML/RARα oncogenic effects (Yoshida, et al. (1996) supra; Raelson, et al. (1996) supra; Nervi, et al. (1998) supra; Zhu, et al. (1999) supra). Hammerhead ribozymes that target PML/RARα have been used to show how PML/RARα degradation signals apoptosis but not differentiation in transfected APL cells that are either RA-sensitive or RA-resistant (Nason-Burchanel, et al. (1998) Blood 92:1758-1767; Nason-Burchanel, et al. (1998) Oncogene 17:1759-1768).